Rho family GTPase are molecular switches that control signaling pathways regulating actin cytoskeleton reorganization, gene expression, cell cycle progression, cell survival, and other cellular processes. Among other functions, they participate in cell cycle and cell division regulation, being also involved in secretion, endocytosis, phagocytosis, membrane traffic and apoptosis. Rho family proteins constitute one of three major branches of the Ras superfamily. Rho proteins share approximately 30 percent amino acid identity with the Ras proteins. At least 23 mammalian Rho family proteins have been identified thus far, including RhoA, Rac1 and Cdc42.
Tumor cells, besides presenting proliferation deregulation, they present alterations in their morphological characteristics and, in the case of metastasis, and they get the ability to pass through tissue barriers. Rho-GTPases play an important role in controlling cell morphology and motility. A compound capable of specifically inhibiting Rho-GTPases activity offers a specific alternative in cancer therapy.
The compound N-(3,5-dimethylphenyl)-N′-(2-trifluoromethylphenyl) guanidine represented by the structural formula (I) is a potent and selective inhibitors of Rho-GTPase cell proteins:

Particularly, the compound of formula (I) can be used to inhibit Rho-related Rac1 GTPase cell protein. Accordingly, the compound of formula (I) as an inhibitor of the Rho-related Rac1 GTPase cell protein can be used to treat diseases mediated by mammalian Rac1 cell proteins, particularly for the treatment of any condition mediated by Rho-GTPase cell proteins such as Rac1 cell proteins.
The preparation and the therapeutic use of the compound of formula (I) has been described in the European Patent number EP2766342.
EP2766342 discloses a process for the preparation of the compound 25 (cf. Example 1) which corresponds to the compound of formula (I) of the present invention. The process disclosed in EP2766342 comprises reacting equimolar amounts of a solution of 3,5-dimethylaniline chlorhydrate and N-(2-trifluoromethyl)phenyl)cyanamide in absolute ethanol at a reflux temperature for 15 h. The crude compound of formula (I) was purified by column chromatography with a mixture of hexane and ethyl acetate in the presence of triethylamine. The purified compound of formula (I) was obtained as a white solid compound showing a melting point of 127° C. However, the European patent EP2766342 does not disclose a process for preparing a crystalline solid form of the compound of formula (I). Furthermore, the use of extreme reaction conditions for a prolonged period of time and the use of non-scaling purification technics such as chromatography causes considerable difficulties for its industrial scale up.
On the other hand, polymorphism is the property of some molecules to assume more than one crystalline form in the solid form. A single molecule may give rise to a variety of crystalline forms (also called “polymorphs”) having distinct physical properties. The existence and physical properties of different crystal forms can be determined by a variety of techniques such as X-ray diffraction spectroscopy, differential scanning calorimetry, infrared spectroscopy and melting point. Differences in the physical properties of different crystalline solid forms result from the orientation and intermolecular interactions of adjacent molecules in the bulk solid. Accordingly, polymorphs are distinct solids sharing the same molecular formula yet having distinct advantageous and/or disadvantageous physical properties compared to other forms in the polymorph family. The existence and physical properties of polymorphs is unpredictable.
One of the most important physical properties of a pharmaceutical compound which can form polymorphs is its solubility in aqueous solution, particularly the solubility in gastric juices of a patient. Other important properties relate to stability, bioavailability, ease of formulation, ease of administration, among others. Since some of the crystalline solid form are more adequate for one type of formulation, and other forms for other different formulations, the development of new crystalline solid forms, such as for example crystalline solid forms (i.e. polymorphs), allows for improving the characteristics of the pharmaceutical formulations comprising them. In addition, depending on the therapeutic indications, one or another pharmaceutical formulation may be preferred.
Especially desirable improvements/advantages of a crystalline solid form of the compound of formula (I) form would include: improvement of physicochemical properties in order to facilitate its manufacture or its formulation; to enhance the absorption and/or the bioavailability; being easily obtainable with more constant physicochemical properties; allowing more flexibility while formulating, or facilitating its formulation; having better dispensability properties, thus allowing better dispersion rates, especially if dispersed in an aqueous physiological surrounding, or reducing hygroscopicity; improving stability; and allowing new routes of administration. Most desirably the new crystalline solid form should combine more than one, or even most of these advantages.
Thus, there is a need to develop a more economical and more easily industrializable process for the preparation of the compound of formula (I), in particular for the preparation of new crystalline solid form of the compound of formula (I) suitable for use in the pharmaceutical industry and, in particular, for the treatment of a condition mediated by Rho-GTPase cell proteins.